Ten years of marketing approvals of anticancer drugs in Europe: regulatory policy and guidance documents need to find a balance between different pressures

Abstract

Despite important progress in understanding the molecular factors underlying the development of cancer and the improvement in response rates with new drugs, long-term survival is still disappointing for most common solid tumours. This might be because very little of the modest gain for patients is the result of the new compounds discovered and marketed recently. An assessment of the regulatory agencies' performance may suggest improvements. The present analysis summarizes and evaluates the type of studies and end points used by the EMEA to approve new anticancer drugs, and discusses the application of current regulations. This report is based on the information available on the EMEA web site. We identified current regulatory requirements for anticancer drugs promulgated by the agency and retrieved them in the relevant directory; information about empirical evidence supporting the approval of drugs for solid cancers through the centralised procedure were retrieved from the European Public Assessment Report (EPAR). We surveyed documents for drug applications and later extensions from January 1995, when EMEA was set up, to December 2004. We identified 14 anticancer drugs for 27 different indications (14 new applications and 13 extensions). Overall, 48 clinical studies were used as the basis for approval; randomised comparative (clinical) trial (RCT) and Response Rate were the study design and end points most frequently adopted (respectively, 25 out of 48 and 30 out of 48). In 13 cases, the EPAR explicitly reported differences between arms in terms of survival: the range was 0 -3.7 months, and the mean and median differences were 1.5 and 1.2 months. The majority of studies (13 out of 27, 48%) involved the evaluation of complete and/or partial tumour responses, with regard to the end points supporting the 27 indications. Despite the recommendations of the current EMEA guidance documents, new anticancer agents are still often approved on the basis of small single arm trials that do not allow any assessment of an 'acceptable and extensively documented toxicity profile' and of end points such as response rate, time to progression or progression-free survival which at best can be considered indicators of anticancer activity and are not 'justified surrogate markers for clinical benefit'. Anticipating an earlier than ideal point along the drug approval path and the use of not fully validated surrogate end points in nonrandomised trials looks like a dangerous shortcut that might jeopardise consumers' health, leading to unsafe and ineffective drugs being marketed and prescribed. The present Note for Guidance for new anticancer agents needs revising. Drugs must be rapidly released for patients who need them but not be at the expense of adequate knowledge about the real benefit of the drugs.

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

“…Apolone and colleagues27 evaluated the evidence base for new cancer drugs approved by the EMA in the period 1995-2004. In that 10 year period the EMA authorised 14 anticancer drugs for 27 indications.…”

Postmarket safety of drugs approved by Health Canada on the basis of clinical and surrogate outcomes: a cohort study

“…Only 2 of the 27 were supported by changes in overall survival, as compared with 13 for response rate, 11 for time to progression or progression-free survival, and 1 for "other." 16 Tumour size does not correlate with overall survival, 19 and the use of progression-free survival as a valid biomarker seems to depend on the type of cancer being treated. [19][20][21] The continued use of surrogate outcomes as the basis for approval of drugs to treat noninsulin-dependent diabetes seems difficult to justify given the lack of correlation between a reduction in concentration of glycated hemoglobin and cardiovascular events.…”

“…Cancer drugs are frequently approved on this basis in multiple jurisdictions. 16,17 Garattini and Bertele 18 looked at 12 oncology drugs approved by the European Medicines Agency from 1995 to 2000. The outcomes for the clinical trials of these drugs tended to be subjective (e.g., "time to progression"), and there was seldom an evaluation of survival or quality of life.…”

Nutzen-Risiko-Bewertung neuer Wirkstoffe als Grundlage für Priorisierungsentscheidungen in der Hämatologie/Onkologie: Methodische Herausforderungen und Lösungsansätze

“…In Zulassungsstudien wurden in der Vergangenheit jedoch häufig Surrogatendpunkte gewählt, anhand derer ein patientenrelevanter Nutzen nicht nachgewiesen werden kann, wie z.B. Tumorprogress oder Ansprechrate [10,16,18] [26]. Schließlich erscheinen Strategien zur Förderung der in der klinischen Forschung täti-gen Nachwuchswissenschaftler wünschenswert, um die aktuell auch im Vergleich zur Grund lagenforschung wenig attraktiven Rahmenbedingungen für diesen Bereich zu verbessern [24].…”